This Program Project Grant application presents a coordinated, interactive group of laboratory projects and a core resource, united by a concern with breast cancer and by the use of mouse models of the human disease. It achieves scientific synergy and an economy of effort by the sharing of existing strains, the collaborative development of new strains (e.g., bi-transgenic mice), the configuration and use of a new core facility for the imaging of mouse tumors, the cooperative discovery and selective use of new methods for the characterization of genotypes and phenotypes, and the design, conduct, and analysis of therapeutic trials in laboratory animals using drugs and other reagents developed within the P01. Because active cancer clinicians are intrinsically involved in these efforts, the knowledge gained In our laboratories will have a direct and substantial impact on clinical thinking, education, and research. Project 1, under Dr. Harold Varmus, examines the determinants of tumor progression in mouse models of human breast cancer and related models of ovarian and islet cell neoplasia. Project 2, under Dr. Joan Massague, concerns the TGF-beta eta signaling pathway. Project 3, under Dr. Neal Rosen, develops the ansamycin antibiotics as therapeutic agents and reagents for the study of cancer biology. Project 4, under Drs. Maria Jasin and Mary Ellen Moynahan, explores the consequences of defective homologous repair incurred through BRCA1 and BRCA2 mutations. Project 5, underDr. Robert Benezra, concerns the Id genes and their relation to neoangiogenesis. An Imaging Core, under Drs. Steven Larson and Juri Tjuvajev, supplies advanced imaging technology to the Projects. Dr. Larry Norton serves as Principal Investigator, Dr. Joan Massague as Co-Principal Investigator, and Dr. Agnes Viale as Coordinator of Molecular Array Technologies.